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Vaccine 26S (2008) L49L58

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

ICO Monograph Series on HPV and Cervical Cancer: Latin America and the Caribbean Regional Report

New Approaches to Cervical Cancer Screening in Latin America


and the Caribbean
Rolando Herrero a, , Catterina Ferreccio b , Jorge Salmern c , Maribel Almonte d,e ,
Gloria Ines Snchez f , Eduardo Lazcano-Ponce g , Jos Jernimo h,i
a

Proyecto Epidemiolgico Guanacaste, Fundacin INCIENSA, San Jos, Costa Rica


Public Health Department, Escuela de Medicina, Ponticia Universidad Catlica de Chile, Santiago, Chile
Epidemiologic Investigation and Health Research Unit, Instituto Mexicano de Seguro Social, Cuernavaca, Mexico
d
Non-communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom
e
Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, London,United Kingdom
f
Infections and Cancer Group, School of Medicine, University of Antioquia, Medellin, Colombia
g
Instituto Nacional de Salud Pblica, Cuernavaca, Morelos, Mexico
h
PATH, Seattle, WA, USA
i
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
b
c

a r t i c l e
Keywords:
HPV
HPV testing
Latin America
Caribbean
Cervical cancer
Screening
Cytology

i n f o

a b s t r a c t
Cervical cancer remains an important public health problem in the Latin America and Caribbean region
(LAC), with an expected signicant increase in disease burden in the next decades as a result of population
ageing. Prophylactic human papillomavirus (HPV) vaccine is currently unaffordable in LAC countries.
However, even if vaccination was implemented, an additional two decades will be required to observe
its impact on HPV related disease and cancer. With some exceptions, cytology-based screening programs
have been largely ineffective to control the problem in the region, and there is a need for new approaches
to the organization of screening and for use of newly developed techniques. Several research groups in
LAC have conducted research on new screening methods, some of which are summarized in this paper.
A recommendation to reorganize screening programs is presented considering visual inspection for very
low resource areas, improvement of cytology where it is operating successfully and HPV DNA testing
followed by visual inspection with acetic acid (VIA) or cytology as soon as this method becomes technically
and economically sustainable. This could be facilitated by the incorporation of new, low-cost HPV DNA
testing methods and the use of self-collected vaginal specimens for selected groups of the population. An
important requisite for screening based on HPV testing will be the quality assurance of the laboratory and
the technique by validation and certication measures.
2008 Elsevier Ltd. All rights reserved.

1. Introduction
Efforts to control cervical cancer in the Latin America and
Caribbean region (LAC) have been largely unsuccessful. Recent estimates predict that if current incidence rates remained unchanged,
by 2025, countries in LAC would face an increase of nearly 75% in
the number of cases solely as a consequence of population ageing.
This could represent more than 50,000 additional cases per year,
raising the total to more than 126,000 with about 60,000 deaths
per year [1].
Prophylactic human papillomavirus (HPV) vaccines will take
years to become affordable as public health interventions in LAC,
and even more time to affect cervical cancer rates [2,3]. Therefore,

Corresponding author. Tel.: +506 2220 3039; fax: +506 2291 0832.
E-mail address: rherrero@amnet.co.cr (R. Herrero).
0264-410X/$ see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2008.05.025

it is imperative for governments to establish cervical cancer screening and treatment programs aimed at preventing the hundreds of
thousands of deaths that will occur in LAC before the vaccine starts
having an impact on the disease.
The basis of programs that have reduced cervical cancer in
developed countries is mass screening with cytology, followed
by colposcopy, biopsy and treatment as needed. Each of these
procedures has important technical limitations, and successful secondary prevention of cervical cancer requires repeated testing
every one to three years and intensive workup procedures, making the multi-visit process very complex and expensive. Although
the elements of successful programs have been known for many
decades, the resources or the political will to make the necessary
investments have been lacking in most developing countries. In
addition, womens health priorities linked to their education and
competing needs have hampered these efforts in low-resource settings.

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R. Herrero et al. / Vaccine 26S (2008) L49L58

Table 1
Performance of single and selecteda two test strategies for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). Guanacaste, Costa Rica
Estrategyb

Sensitivityc

Specicityd

Youdens Indexe

95% Condence Intervale

HPV (+)
Liquid-based Cytology ( ASC-US)
Pap Smear ( ASC-US)
Cervigram ( A)
Pap Smear ( HSIL) or HPV (+)
Liquid-based Cytology ( HSIL) or HPV (+)
Cervigram ( P2) or HPV (+)
Liquid-based Cytology ( ASC-US) or Cervigram ( P0)
Pap Smear ( HSIL) or liquid-based cytology ( ASC-US)
Pap Smear ( LSIL) or Cervigram ( P0)

85.3
87.5
63.0
61.7
90.7
90.5
89.7
93.2
86.5
74.5

88.2
87.8
93.7
84.8
87.8
88.0
88.1
83.9
87.6
90.9

0.74
0.74
0.57
0.46
0.79
0.78
0.78
0.77
0.74
0.65

0.670.80
0.670.80
0.480.66
0.370.56
0.730.84
0.730.84
0.720.84
0.720.82
0.680.81
0.570.74

ASC-US: Atypical squamous cells of undetermined signicance; HSIL: High-grade squamous intraepithelial lesions; LSIL: Low-grade squamous intraepithelial lesions. A:
Atypical.
Reproduced from Ferreccio C et al. 2003 [7].
a
For each of the six possible two-technique combinations, the table shows the performance for the cut-points with the highest accuracy as measured by Youdens index.
b
There were three possible thresholds for conventional and liquid-based cytology (ASC-US, LSIL, HSIL), ve possible thresholds for Cervigram [Atypical (A), Positive 0 (P0),
Positive 1 (P1), Positive 2 (P2), Positive 3 (P3)], and a single threshold for HPV DNA testing (positive versus negative). Techniques were considered singly and in pairs at all
thresholds. Two kinds of combinations were evaluated, either requiring both techniques to be positive or at least one. Overall, there were 112 strategies considered, which
were ranked in order of decreasing Youdens index.
c
Sensitivity calculated as the percentage of cases of >=CIN3 detected by the screening strategy.
d
Specicity calculated as the percentage of women without CIN3 or cancer who tested negative by the screening strategy.
e
Youdens index calculated as sensitivity plus specicity (expressed as proportions) minus 1.00, with 95% condence interval. The values range theoretically from 1.0
(perfect) to 0.0 (randomly useless) to 1.0 (always wrong).

New approaches to cervical cancer screening are needed to overcome the technical limitations, simplify the process and render it
more feasible and acceptable to women in limited resource areas.
Several of these approaches take advantage of the current understanding of the natural history of the disease and new technological
developments (e.g., HPV DNA testing) are being evaluated in trials
and demonstration projects. These approaches need to be already
under active discussion among public health decision makers and
womens organizations for timely implementation.
Several institutions in LAC are conducting research to evaluate
some of these new methods. Although in the Caribbean region there
are limited data on screening, the burden of disease is similar to
Latin American nations and cervical cancer screening programs for
secondary prevention are also necessary. In this article, we summarize the most salient research efforts and discuss some potential
new approaches to cervical cancer control in different settings of
LAC according to their level of development and infrastructure.
2. Research activities on screening methods in Latin
America
2.1. Evaluation of screening techniques in Costa Rica: the
Guanacaste Project
In the population-based cohort study conducted in Guanacaste
in 199394 [4], the performance of conventional cytology, liquidbased cytology (LBC) [5], HPV testing for 13 carcinogenic types
with MY09-11 polymerase chain reaction (PCR), Hybrid Capture
2 (HC2), Qiagen Gaithersburg, Inc., MD, USA (previously Digene
Corp.) and CervigramTM , National Testing Laboratories, Fenton, MO
[6] were evaluated. The tests were applied concurrently to more
than 8,500 women [7]. The nal reference diagnosis for study
endpoint was histologically-conrmed cervical intraepithelial neoplasia grade 3 or worse (CIN3+) at enrollment or during follow-up.
Conventional cytology was interpreted in Costa Rica, the other
techniques in the United States of America (USA). Sensitivity and
specicity of each technique were analyzed individually and in
paired combinations, using Youdens index as a summary measure
of test accuracy (Table 1).
As single techniques, LBC or PCR HPV DNA testing were signicantly more accurate than cytology or Cervigram, particularly

among older women. Cervigram was the least accurate test of any.
Considering two tests in combination with either LBC or PCR HPV
testing, accuracy was not substantially increased in comparison to
either test alone. A possibly useful synergy was observed between
conventional cytology and Cervigram, suggesting that these techniques together, cytological and visual may provide an increased
benet.
The sensitivity of LBC was considerably higher than that of
conventional cytology, although the tests were not interpreted by
the same cytopathologists. On the other hand, HPV testing and
LBC had lower positive predictive values than conventional cytology (Table 2). Cytological techniques, highly observer-dependent,
performed better than usually reported, a poorer performance is
expected in real life than in this highly controlled research study.
The performance of HC2, the only Food and Drug Administration
(FDA)-approved HPV testing method, which detects the combined
presence of 13 cancer-associated HPV types (HPV-16, 18, 31, 33, 35,
39, 45, 51, 52, 56, 58, 59, and 68) was also evaluated. This methodology had a testing sensitivity of 88.4% and a specicity of 89.0% for
high-grade lesions and cancer (all cancer cases tested HPV positive
with HC2) [8].
The Guanacaste study demonstrated that HPV testing and possibly LBC are more sensitive than conventional cytology. In LAC,
many women will have few contacts with screening programs,
making a screening test of high sensitivity and negative predictive
value preferable. HPV tests and LBC accomplished that requirement in Guanacaste, but the former is easier to standardize and
is highly reproducible, possibly providing more consistent results
in different scenarios. Better sensitivity of HPV testing has been
demonstrated in multiple studies, but that of LBC remains controversial [9].
2.2. Evaluation of screening techniques in San Martn. Per: the
TATI Project
The TATI project (Spanish acronym for screening and immediate treatment) was conducted to investigate screening tests that
are potentially more appropriate in high incidence areas with limited resources [10]. More than 30,000 women aged 2549 years;
with an intact uterus and no past history of conization were
screened with visual inspection with acetic acid (VIA) and con-

R. Herrero et al. / Vaccine 26S (2008) L49L58


Table 2
Positive and negative predictive values for single and selecteda two-test strategies
for the detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+).
Guanacaste, Costa Rica 2003
Strategyb

Positive predictive
valuec

Negative predictive valued

Liquid-based cytology
(ASC-US)
HPV (+)
Pap Smear (ASC-US)
Cervigram (A)
Pap Smear (HSIL) or HPV (+)
Liquid-based cytology (HSIL) or
HPV (+)
Cervigram (P2) or HPV (+)
Liquid-based cytology
(ASC-US) or Cervigram (P0)

8.5%

99.8%

8.6%
11.5%
4.9%
8.8%
9.0%

99.8%
99.5%
99.4%
99.9%
99.9%

8.8%
7.0%

99.9%
99.9%

ASC-US: Atypical squamous cells of undetermined signicance; HSIL: High-grade


squamous intraepithelial lesions.
Reproduced from Ferreccio C et al. 2003 [7].
a
For each of the six possible two-technique combinations, the table shows the
predictive values for the cut-points with the highest accuracy as measured by
Youdens index.
b
There were three possible thresholds for conventional and liquid-based cytology
(ASC-US, LSIL, HSIL), ve possible thresholds for Cervigram [Atypical (A), Positive
(P0), Positive 1 (P1), Positive 2 (P2), Positive 3 (P3)], and a single threshold for HPV
DNA testing (positive versus negative). Techniques were considered singly and in
pairs at all thresholds. Two kinds of combinations were evaluated, either requiring
both techniques to be positive or at least one. Overall, there were 112 strategies
considered, which were ranked in order of decreasing Youdens index.
c
Positive predictive value was calculated as the percentage of women with a
positive screening result that had CIN3 or cancer diagnosed.
d
Negative predictive value was calculated as the percentage of women with a
negative screening result that did not have CIN3 or cancer diagnosed.

ventional cytology. A subgroup of 5,435 women was additionally


screened with LBC and HC2 HPV testing in 2001. Women were
examined by midwives, who collected the samples before performing VIA. Cytology was read locally, LBC in Lima and HC2 in London.
VIA positive women were subsequently examined by a doctor
with VIA aided by a magnication device (VIAM) and treated with
cryotherapy if appropriate or referred for further evaluation and
treatment. Women with low-grade or negative LBC but positive
HPV were re-screened at 618 months. Women with high-grade
squamous intraepithelial lesions (HSIL) with any method and those
with low-grade squamous intraepithelial lesions (LSIL) or HPV positive on second testing were also referred to colposcopy.
Positivity rates of VIA, conventional cytology for atypical squamous cells of undetermined signicance or worse (ASC-US+), LBC
(for ASC-US+) and HPV testing with HC2 (cut-off point: 1 relative
light unit (RLU)) were 24.2%, 1.8%, 16.9% and 12.6%, respectively. The
proportion of women with abnormal LBC increased slightly with
age, mainly because of increasing rates of CIN2 or worse (CIN2+).
Abnormal conventional cytology also increased with age, while VIA
and HPV positivity decreased with age (Table 3).

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A total of 1,881 women (84% of 2,236 VIA positive women)


accepted VIAM/cryotherapy: 79 had carcinoma in situ or cancer
(CIS+), 27 CIN3 and 42 CIN2 on histology. The authors estimated
a further 6.5 cases of CIS+ in women without a biopsy. HPV testing
was the most sensitive (89.4%) for detecting CIN3+, followed by LBC
ASC-US+ (76.6%), with corresponding specicities (for no CIN2+) of
only 89.3% and 83.7% (Table 4). The sensitivity of VIA for CIN2+ was
54.9% (specicity: 76.7%) and that of conventional cytology 26.2%
(specicity: 98.7%). For CIN3+, the sensitivity of VIA was 48.1 and
that of conventional cytology 33.6%.
VIA positivity in samples collected by 20 midwives ranged
from 7%43%, and was inversely related to the number of VIA
tests performed, indicating that experience improves specicity
[11]. Because triage by physician-VIAM increased the specicity of
midwife-VIA considerably, a subsequent study in San Martin compared triage by physicians randomized either to VIA or VIAM, which
found no signicant advantage for VIAM [12].
While VIA detected just over 50% of high-grade disease, cytology
detected only about 25% of the cases. Both cytology and VIA suffer
from their dependence on human skills and judgment. VIA gives
immediate results, but requires training and supervision, although
there is no standardized method of training or quality assurance for
VIA.
The TATI project reached only 40% of women, far from its
80% programmed target, demonstrating that even a simple and
inexpensive method like VIA has important logistic limitations
in real-life conditions in LAC [13]. Furthermore, often immediate
treatment was not performed because the doctor was not available
or the women could not wait or simply refused to be treated.
VIA could be a good primary care option for an immediate
intervention in populations not covered by conventional screening programs to identify precancerous lesions. The fast results may
increase compliance with follow-up. Cryotherapy is easily implemented in primary care settings, with good acceptability by women
and providers. An evaluation of its efcacy in TATI one year after
treatment showed that 70% of CIN3 were successfully treated. However, only 10.1% of women treated had CIN2 or more severe lesions,
revealing substantial over-treatment [14]. A ve-year follow-up
colposcopic examination is planned to evaluate long term effectiveness.
HPV testing is feasible in low-resource settings and offers the
best prospect for cervical screening, but it is currently costly and
will require establishing laboratory and transport networks. The
introduction of the faster QIAGEN HPV test based on Fast HPV
technology (Qiagen Gaithersburg, Inc., MD, USA (previously Digene
Corp.)), currently under development, will be of great interest.
2.3. Evaluation of vaginal self-sampling in Chile
In the TATI project, more than 50% of eligible women did not
participate despite intensive outreach efforts. Many invasive cervi-

Table 3
Positivity rates of screening with different methods among 5,435 women aged 2549 years in the TATI project
Age

N total

25-29
30-34
35-39
40-44
45-49
All ages

1,480
1,463
1,223
769
500
5,435

VIA

PAP smearsa (ASC-US+)

Liquid-based cytologya (ASC-US+)

HPV testing (1 RLU +)

366
376
311
166
98
1,317

24.7
25.7
25.4
21.6
19.6
24.2

16
25
22
21
13
97

1.1
1.7
1.8
2.7
2.6
1.8

227
231
228
134
99
919

15.3
15.8
18.6
17.4
19.8
16.9

229
182
145
88
43
687

15.5
12.4
11.9
11.4
8.6
12.6

VIA: Visual inspection with acetic acid; RLU: Relative light unit; ASC-US: Atypical squamous cells of undetermined signicance.
Adapted from Almonte M et al. 2007 [10].
a
Percentage including those with missing or inadequate test samples.

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R. Herrero et al. / Vaccine 26S (2008) L49L58

Table 4
Sensitivity, specicity and positive predictive values of screening tests in 5,435 women, TATI Project
Sensitivity (95% Cl) forb

Specicity (95% Cl) forb

PPV (95% Cl) forb

Moderate Dysplasia+ (N = 174.8)

Severe Dysplasia+ (N = 121.2)

CIS+ (N = 85.5)

<Moderate Dysplasia (N = 5,260.2)

Moderate Dysplasia+

VIA

54.90
(47.062.7)

48.06
(38.757.3)

41.18
(30.552.0)

76.70
(75.577.8)

6.65
(5.38.0)

VIA + M

42.79
(34.750.9)

36.24
(27.245.6)

31.36
(21.341.6)

90.96
(90.291.7)

12.40
(9.615.2)

PAPa

26.21
(19.033.6)

33.61
(24.442.8)

42.54
(31.553.8)

98.68
(98.399.0)

37.93
(28.147.5)

69.66
(62.276.8)

76.57
(68.184.2)

80.28
(71.188.7)

83.71
(82.784.7)

11.69
(9.613.8)

64.70
(56.872.0)

73.36
(60.677.6)

77.32
(67.786.0)

86.69
(85.787.6)

13.07
(10.615.5)

HC2 HPV testing


1RLU
77.27
(70.483.5)

89.42
(83.394.6)

95.78
(91.199.4)

89.32
(88.590.1)

17.95
(15.020.9)

LBC
ASCUS
LSIL

2RLU

72.77
(65.679.5)

84.96
(78.191.2)

89.85
(82.995.7)

90.45
(89.791.2)

18.73
(15.621.9)

4RLU

70.02
(62.776.9)

83.0
(75.889.5)

88.49
(81.494.7)

91.58
(90.892.3)

20.09
(16.723.5)

VIA or PAPa

66.76
(58.874.4)

64.51
(55.273.5)

62.36
(51.072.9)

76.34
(75.177.6)

7.99
(6.49.6)

CIS: Carcinoma in situ; PPV: Positive predictive value; VIA: Visual inspection with acetic acid; VIA + M: VIA aided by a magnication device after a VIA positive exam; RLU:
Relative light unit; ASC-US: Atypical squamous cells of undetermined signicance; LSIL: Low-grade squamous intraepithelial lesions; CI: Condence interval.
Reproduced from Almonte M et al. 2007 [10].
a
PAP = Conventional cytology ASC-US or worse.
b
Histology was carried out in a laboratory in Lima and was reported using a standard Peruvian classication (which includes moderate and severe dysplasia, carcinoma
in situ and cancer). Roughly speaking, severe dysplasia and carcinoma in situ should correspond to CIN3 and moderate dysplasia to CIN2.

cal cancers are found in women who have never been screened.
An alternative for women who reject the pelvic examination is
self-collected (SC) vaginal sampling obtained at home. In a nationwide study of Chilean women in 2003, there was high participation
(83.1%) by patients and health workers, providing samples adequate
for HPV testing. The most frequent high-risk HPV types detected
from vaginal samples were similar to those types identied in previous studies using cervical samples [15].
A follow-up study (20062009) of women from a prevalence
survey [16] used self-sampling at home and cytology at the clinic,
with participation rates of 91.4% and 70.7%, respectively. Preliminary results show a very high rate of -globin positivity (96.2%
and 97.5%, respectively) indicating that SC vaginal samples are of
very good quality, comparable with cervical samples. A higher rate
of HPV detection in the vaginal than in the cervical samples was
noted (23.2% and 14.7%, respectively). The impact of the increased
HPV detection on the sensitivity and specicity to detect cervical
cancer precursors needs to be investigated.
Both population-based studies demonstrated that self-sampling
can be easily incorporated in LAC as part of an HPV based screening program and it has the advantage of allowing better allocation
of human resources and increasing access to certain subgroups of
women who are isolated or reluctant to be examined. Its main

limitations are inherent to the current HPV testing itself: cost and
limited specicity.
2.4. HPV testing as primary screening at the Mexican Institute for
Social Security (IMSS), Morelos, Mexico
To evaluate whether HPV testing is more effective than cytology
[17], SC, HPV test clinician-collected (CC) HPV test and cytology
were compared. The HPV HC2 test was performed both on the SC
and CC samples. All women attending screening at 23 health units
were invited in 1999. Women with history of CIN2/3 or cancer, previous hysterectomy, or pregnant were excluded. A total of 7,868
women between the ages of 15 and 85 (median age = 41 years)
participated (response rate: >95%).
Detection rates of high-risk HPV types in the SC and CC specimens were 11.6% and 9.4%, respectively. The relative sensitivity of
cytology to detect CIN2/3 or cancer was lower (59.4%), as compared
to 71.3% (p = 0. 008) for SC, and 93.1% (p = 0.0001) for CC (Table 5).
The relative specicity was 98.6%, 90.4%, and 92.8% for cytology, SC and CC, respectively. Negative predictive values were 99.4%,
99.5% and 99.9%, and colposcopy referral was 2.8%, 11.0% and 6.7%.
HPV testing showed higher sensitivity than cytology and the
CC HPV test showed the highest sensitivity for detection of cer-

Table 5
Performance of the Pap smear, HPV self-collected (SC) and HPV clinician-collected (CC) testing strategies for cervical cancer screening in Mexico
Test

Pap smear

HPV-SC

HPV-CC

Pap smear and HPV-SC

Pap smear and HPV-CC

Sensitivity (95% CI)


Specicity (95% CI)
Positive Predictive Value (95% CI)
Negative Predictive Value (95% CI)

59.40 (49.1668.92)
98.59 (98.2998.84)
36.36 (29.1244.24)
99.44 (99.2499.59)

71.28 (61.2979.30)
90.37 (89.6891.03)
9.09 (7.2211.36)
99.57 (99.3799.70)

93.06 (85.7596.92)
92.82 (92.2193.39)
14.89 (12.2517.97)
99.89 (99.7899.95)

88.34 (80.0593.61)
89.11 (88.3889.90)
9.86 (8.0312.03)
99.82 (99.6899.90)

97.18 (91.1499.30)
91.52 (90.8692.13)
13.38 (11.0416.11)
99.95 (99.8699.98)

HPV-SC: Self-collected HPV HC2 test; HPV-CC: Clinician-collected HPV HC2 test; CI: Condence interval.
Reproduced from Salmeron J et al. 2003 [17].

R. Herrero et al. / Vaccine 26S (2008) L49L58

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Table 6
Estimated detection rates of underlying high-grade squamous intraepithelial lesion (HSIL) or cervical cancer by a conventional cytology test and a self-collected (SC) HPV test
Estimated detection rate

Cervical cytology

SC vaginal sample at home

Rate of detection of CIN2+


Rate of detection of invasive cancer

244 100,000 women older than 25 years


37 100, 000 women older than 25 years

725 100,000 women older than 25 years


54 100, 000 women older than 25 years

SC: Self-collected; CIN2+: Cervical intraepithelial neoplasia of grade 2 or worse.


A study of 22,582 women older than 25 years in Mexico.
Lazcano-Ponce E et al. submitted 2008.

vical lesions, with a signicantly higher negative predictive value


than cytology (99.9% versus 99.4%, respectively). Overall, these ndings suggest that CC samples for HPV testing may be an effective
alternative that can increase sensitivity of cervical cancer screening.

2.5. Self-sampling and HPV testing among insured women in


Mexico
Another community study was conducted to compare performance of SC HC2 HPV testing with cytology, including 22,582
women in three states (Lazcano-Ponce E et al. submitted 2008).
Women were 25 years or older, excluded if pregnant or hysterectomized and randomly assigned to self-collection at home or
cytology at the clinic.
A total of 8,207 women were in the self-collection group and
13,660 in the cytology group. Participation rate for self-collection
was 96.3%. Prevalence of high-risk HPV was 9.7% in the selfcollection arm (n = 802). These women were referred to colposcopy
and 221 biopsies were taken, 66 women had histologicallyconrmed CIN2/3 and ve women had invasive cancer.
Of the 13,660 women who had cytology, 169 had high-grade
lesions, corresponding to 1.24% of the population, and were
referred to colposcopy. Fifty-ve women had a biopsy and 32 had

histologically-conrmed CIN2+. Cytology had a CIN2/3 detection


rate of 244 per 100,000 among women 25 and older, whereas in
the selfcollection group detection rate was 725 per 100,000. Corresponding detection rates for invasive cancer were 54 per 100,000
for SC with HPV test and 37 per 100,000 for cervical cytology
(Table 6).
This work demonstrated that SC HC2 HPV testing is feasible and
could increase coverage and detection of lesions, particularly where
infrastructure is not available or among women who are reluctant
to be examined. It can be used in large scale programs because it can
be semi-automated and does not require a cold chain. However, it
requires appropriate training and education of the public about the
signicance of an HPV positive test. Both HPV testing and cytology
showed good positive predictive value to identify cervical cancer,
but HPV testing detected more lesions.

2.6. Comparison of HPV testing and cytology strategies among


IMSS population, Mexico, 20052009
A community-based trial is underway (20042009) among
50,000 insured women between 30 and 64 years in several states
(Lazcano-Ponce E et al. submitted 2008). The main objectives of
the trial are: (1) to study the impact of HPV testing and cytology
in a cohort of HPV positive women and a group of 2,000 women

Fig. 1. Screening and follow-up algorithms in the 50,000-women community trial among women from the Mexican Institute of Social Security (20052009).
Percentages and absolute numbers are the expected for each group and branch. Pap: Papanicolaou test; HPV: HPV DNA test; TX: treatment.
Source of data: Lazcano-Ponce E et al. submitted 2008.

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R. Herrero et al. / Vaccine 26S (2008) L49L58

previously negative for HPV and cytology; (2) to dene persistent


infection and its impact on cervical cancer screening programs after
the initial HPV test.
Women attending cytology screening are being offered an HPV
test in addition to cytology, and according to the results of their tests
they will be included in one of three follow-up groups according
to pre-established algorithms (Fig. 1). Women in the rst group
would be those with an abnormal cytology independent of HPV
result. It is estimated that 2.5% of these women will be referred
to colposcopy. If evaluation is normal, women will be transferred
to the third group (see below). Women in group two have normal
cytology but are HPV positive. It is estimated that around 9% of
the women will be included in this group. These women will be
followed with HPV testing at months 12, 24 and 36 after the initial
HPV test, and those testing positive in any of those repeat tests will
be assigned to either cytology tests every three years or colposcopy.
Women with abnormal cytology will be referred to colposcopy. In
the third group, women have normal cytology and are HPV negative.
A random sample of 2,000 women from this group will be followed
with HPV testing and cytology and referred to colposcopy at 3, 4
and 5 years. The results of this demonstration project will provide
guidelines to dene strategies that could be applicable in LAC.
2.7. Evaluation of VIA, visual inspection with Lugols iodine (VILI),
cervical cytology and HPV testing in Brazil and Argentina (The
Latin American Screening Study (LAMS))
Another investigation of the performance of different screening methods was conducted among 11,834 women 1860 years old
attending screening clinics in three centers in Brazil (Campinas,
Porto Alegre and Sao Paulo) and one in Argentina (Buenos Aires).
Women were screened with VIA, VILI, conventional cytology and
HPV testing with HC2. Partial results have been published for 11,834
women who were examined with VIA, 2,994 who were examined
with VILI, 10,138 who had cytology and 4,195 who had HPV testing
[18].
For CIN3+, the sensitivity of VIA was 45.4% and the specicity
89.5%, VILI had a sensitivity of 65.3% and a specicity of 77.9%,
cytology with a threshold of LSIL had a sensitivity of 64.0% and
a specicity of 98.4%, and HPV testing with HC2 had a sensitivity
of 97.0%, with a specicity of 86.0%. As expected, combinations of
methods would improve sensitivity at the expense of specicity.
3. Proposal for screening in Latin America and the
Caribbean
Screening programs require a series of elements that are, in
aggregate, more important than the screening technique used. Success is dependent on having an integrated program incorporating,
among others, the elements presented in Table 7. Essential components of screening programs that are not discussed in detail in this
article but require special attention are colposcopic evaluation of
women with abnormal tests and the development of corresponding
algorithms for diagnosis and treatment, in addition to infrastructure and expertise for histopathologic diagnosis.
The most cost-effective programs are those that reduce the
number of visits or improve follow-up and that rely less on sophisticated laboratory infrastructure than conventional cytology [19].
Different countries have different needs and capabilities, and the
programs need to be tailored to the degree of socio-economic development of the regions, including their health infrastructure and
human resources.
HPV is a necessary cause of cervical cancer and its precursors and
practically all cases must be preceded by HPV infection. Therefore,

Table 7
Elements required for a successful screening program
Central coordination
Information system
Quality assurance of all aspects of the program
Uniformity of activities and operating procedures
Denition of target groups (avoidance of low risk groups, e.g. very young women)
Denition and adherence to screening intervals
High coverage of the population selected
Adequate follow up of abnormalities
Assurance of timely treatment of lesions detected
Consideration of other womens health needs in the area
Communication and educational strategies
Evaluation
Adoption of a clinically validated screening test
Adoption of a clinically validated triage and diagnostic test
Public and sustainable funding scheme

a sensitive and reproducible HPV test should detect the virus in all
women with disease or destined to develop it in the few years following a positive test. However, HPV is very common, particularly
among younger women, and more than 90% of infections regress
within two years regardless of the HPV type [20]. The real precursor
of cervical cancer is persistent HPV infection, which can be detected
with one of the following methods alone or in combination: (1)
testing women repeatedly for HPV; (2) restricting screening to
age groups where infections are more likely to represent persistent infections; or (3) detecting cytologic or visual abnormalities
associated with persistent infections. A series of potentially useful biomarkers including expression of E6/E7 transcripts, p16 and
others are under investigation and are discussed elsewhere in this
Monograph [21]. We discuss below some of the current screening
strategies that are currently considered to have potential to improve
the current programs.
3.1. Cytology as primary screening
Cytology has low and variable sensitivity, requires multiple visits and has proven extremely difcult to implement successfully in
LAC. Countries initiating programs need to consider new alternatives. However, screening with cytology is in use in many countries
in LAC, and transition to any different technique would take years.
In the meantime, where cytology is being used, quality assurance
must be emphasized. Quality assurance is more feasible when specialized staff are concentrated in as few laboratories as possible,
to assure uniformity of training, procedures, recommendations
to clinicians etc. In Costa Rica, for example, as part of the reorganization of the screening program, cytology laboratories were
centralized in 1998 into one large National Cytology Laboratory
that currently receives close to 400,000 smears a year. Since then,
cervical cancer incidence and mortality have decline signicantly,
probably as a consequence of this and other improvements of the
screening program (Fig. 2). In countries where centralized laboratories are not possible, cervical cancer screening guidelines should
include regulations for external and internal quality control, as well
as external regulatory supervision.
Another important aspect is the threshold for referral to colposcopy of lesions detected by cytology. LSIL is the cytological
manifestation of an acute HPV infection and not a true cancer precursor [22], and the vast majority of such lesions disappear in a
few months. When they are referred for colposcopy, they generate a large burden of referrals and treatment. When appropriate
follow-up can be assured, repeat cytology after six months should
be considered. Several organizations have modied their guidelines
in this regard, including the American Society for Colposcopy and
Cervical Pathology (ASCCP), which now recommends repeat cytol-

R. Herrero et al. / Vaccine 26S (2008) L49L58

L55

Fig. 2. Standardized mortality rates of cervical cancer in Costa Rica, 19802005. Instituto Nacional de Estadstica y Censo, Registro Nacional de Tumores.

ogy for adolescents and post-menopausal women with LSIL [23].


Similarly, a conservative approach of repeat cytology can be used
for evaluation of ASC-US, as recommended by ASCCP, to concentrate
limited resources on the colposcopic evaluation and treatment of
women with HSIL.
On the other hand, assurance of complete follow-up and treatment of signicant abnormalities (HSIL) is more important and
constitutes an essential component of the program. The establishment of high quality referral centers for colposcopy and the
consideration of high-grade cytology as a public health priority are
fundamental if a cytology-based program is to succeed. Women
with previous HSIL cytology results still need to be referred to colposcopy if they have not been evaluated.
Furthermore, approaches that reduce the number of visits
should be considered, including see and treat of women with HSIL
that have evidence of high-grade lesions on colposcopy. A study
conducted by the Peruvian Cancer Institute enrolled 639 patients
referred because of a positive cytology [24]. Women were evaluated with repeat cytology and colposcopy at the rst visit and a
decision was made on whether to treat the same day or not. This
strategy allowed evaluation and treatment of 69% of patients with
CIN referred for colposcopy without major complications.
The use of liquid-based, instead of conventional, cytology has
generated enthusiasm and it has become the preferred method
in the USA and other developed countries, including the United
Kingdom (UK) where it was recently adopted by the National Program. Several studies showed improved sensitivity, including those
described above conducted in LAC, although in Guanacaste and
TATI slide interpretation for LBC and conventional cytology was not
done by the same cytopathologists. A large trial conducted in Italy
showed no increased sensitivity of LBC compared to conventional
cytology, but detected an important reduction in the number of
inadequate tests [25]. LBC has the advantage of permitting reex
testing for HPV. However, there is a signicant increase in costs
using this method and its advantages are still questionable [9]. At
this time we do not consider changing to LBC a priority for programs in LAC until cost benet is proven or a less expensive LBC
technology is available.
3.2. HPV testing as primary screening test
HPV testing is a highly reproducible technique, and it clearly
shows higher sensitivity than cytology for detecting cervical cancer
precursors [26]. A meta-analysis reported in this Monograph indicates a sensitivity close to 95% for detection of CIN3+ [27]. It should
be noted however, that some reports from developing countries

(India, Brazil, and Zimbabwe) have shown lower sensitivity, pointing to technical difculties in those settings [28]. HPV testing has
been approved by the USA FDA as an adjunct to cytology among
women aged 30 and older, where specicity is highest, allowing
for an extension of the screening interval given the very high negative predictive value of a negative HPV combined with negative
cytology. In younger women infection is highly prevalent and normally clears within the rst few months [29]. However, the ideal
age needs to be adapted to the age of initiation of sexual activity and the epidemiology of cervical cancer precursors of different
regions.
Several studies have been conducted in LAC [7,10,30,31], and it
has been shown that the predictive value of a negative HPV test is
very high (9798%) [32]. In this context, screening intervals may
be increased for HPV negative women, because their risk of developing cervical cancer over the following 510 years is very low
[33]. Also screening could be stopped or intervals increased among
repeatedly HPV negative women over 50.
In two recent large randomized trials comparing cytology alone
with cytology plus HPV testing conducted in The Netherlands [34]
and Sweden [35], a signicant reduction in the number of CIN3+
lesions after 46 years of follow-up in the groups receiving both
tests compared to the group receiving only cytology was observed,
further indicating that screening intervals could be extended.
It is clear that combining HPV and cytology represents an
improvement that leads to earlier detection of precursor lesions
and allows extension of the screening interval, but an approach
combining HPV and cytology would be costly and appears unrealistic for LAC. HPV testing alone followed by colposcopic referral
would produce a large number of referrals, given that it has limited specicity, and therefore HPV testing followed by triage with
a more specic test has been proposed (see below).
A note of caution is necessary when recommending HPV testing
for use in screening programs. At this time, the only fully validated
and FDA approved HPV testing method, which has been used in
most of the studies is HC2. It is highly desirable to have additional
comparable tests, but they need to be properly validated and certied to assure the anticipated benets of relying on a new technique.
The Pan American Health Organization (PAHO) and other international organizations would be expected to play an important role
in dening guidelines, negotiations for purchase of reagents and
certication of laboratories.
The high cost and relative technical complexity of HC2 make
it currently unrealistic for low-resources settings. A new simpler,
faster HPV test is being developed by PATH (Seattle, USA) in collaboration with Qiagen Gaithersburg, Inc., MD, USA (previously Digene

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R. Herrero et al. / Vaccine 26S (2008) L49L58

Corp.) for low-resources areas. This will provide results within a


couple of hours with similar sensitivity and specicity to HC2, but
at a much lower price (Screening Technologies to Advance Rapid
Testing (START) Project [36]).
Although this new HPV test opens possibilities for one-visit
screening-treatment programs, a study of options for adequate
delivery and introduction of the test in low-resources settings
is currently under evaluation (START-UP Project, PATH), as well
as approaches for immediate diagnosis with a second test (VIA)
to increase specicity, and to allow immediate treatment with
cryotherapy.
The social and psychological consequences of HPV testing need
to be considered in different settings, and uniform approaches to
education and counseling need to be developed. As shown in some
of the studies discussed above, self sampling could be a good strategy for women who live in hard to reach areas or who refuse vaginal
examination.
After widespread introduction of HPV vaccines, HPV testing will
become an even more important screening tool, to focus screening
programs on women at highest risk [37,38]. A discussion of the
integration of vaccination and screening is discussed in another
article of this issue [39].
An effort to evaluate acceptability, feasibility, utility and barriers
for introduction of HPV testing is underway in Colombia. Perceptions about current knowledge on the role of HPV in cervical cancer
and about HPV testing for cervical cancer prevention were investigated in a survey among 449 women from ve centers in Medellin,
Colombia [40].
Women were highly knowledgeable about the purpose and benets of cytology screening, but knowledge about HPV was very poor.
Women of all ages had a very good knowledge of cytology (Chisquare for trend p = 0.1496), but only 8% of participants knew that
HPV causes cervical cancer and that it is sexually transmitted. Limited knowledge about HPV was higher in 1828 year old women
(88%) than in women 49 years and older (72%), (p = 0.003).
Likewise, of 146 college students (mean age 20 years old) interviewed in a local university, around 85% were unaware of the
diseases caused by HPV including cervical cancer and did not understand that this virus is sexually transmitted [41].
Currently the group at the University of Antioquia is designing
studies to evaluate HPV knowledge of the natural history of cervical
cancer and its prevention among healthcare providers.
3.3. VIA as primary screening test
During the last two decades there have been many experiences
with VIA as a primary screening test, some of them showing very
high sensitivity [4244]. A recent large community randomized
trial in India among women aged 30-59 years showed a signicant reduction in incidence (25%) and mortality (35%) over 6 years
among women screened with VIA [45].
Several studies conducted in LAC did not show high sensitivity
for VIA [10,18,46]. A possible explanation for the discrepancies may
be conrmation bias, because in some of the studies, colposcopy
was used as the gold standard, and CIN2+ lesions missed by VIA
(false negatives) are also more likely to be missed by colposcopy.
Additionally, in some of the initial studies the providers worked
almost exclusively on cervical cancer screening with VIA, while in
real life, they have multiple medical and public health responsibilities besides cervical cancer screening.
Another limitation of VIA is the fact that it has low specicity, in
the range of 49-86% [47], and an important fraction of women may
have false positive results leading to over-treatment.
Health workers should be aware not only of the advantages of
VIA (inexpensive, relatively easy to train and perform, and immedi-

ate results), but also of its limitations such as low sensitivity, poor
specicity and the need of frequent screenings (13 years intervals). VIA requires signicant training and supervision. Despite its
limitations, VIA can be a good alternative in areas where other techniques are not available or have not been successful (poor coverage,
decient quality, etc.), and it could serve as an initial platform to
develop screening activities that can later incorporate more effective techniques.
3.4. HPV testing followed by Pap smear
Approximately 5 to 20% of women are HPV positive [48]. Therefore, more than 80% of all women screened are HPV negative and
have very low-risk of cervical neoplasia in the following 510 years
[33]. A screening algorithm with HPV testing as the initial screening test, followed by cytology of HPV positives, which is a more
specic test, has been proposed [27,37]. Since well-trained cytologists and cytopathologists are scarce, those resources could be
employed for secondary evaluation of HPV positive women. The
main limitation of using Pap smear after HPV testing, in addition to
its limited sensitivity and dependence on human factors for quality,
is that unless the system is organized to collect both specimens at
the same time (reex testing), the results are not immediately available and women should have at least two visits before colposcopy
and treatment.
Women with negative cytology would need to be re-screened
with HPV testing at 612 months and if persistently positive
referred to colposcopy. Women with normal colposcopy would also
require close follow-up with repeat HPV testing. Where LBC is used,
reex testing is facilitated and cytology can be done on the same
specimen collected for HPV testing. This approach could also be
feasible where conventional cytology is used if both specimens are
collected at the same visit. In areas of LAC where cytology screening
has achieved demonstrated efcacy, this strategy could be implemented in demonstration projects.
3.5. HPV testing followed by VIA
Similar to the strategy described for HPV plus cytology, VIA could
be performed only in HPV positive patients, a strategy with the
advantage of saving time and one clinic visit. There are two possible
uses for VIA in this approach, triage and diagnosis.
The rationale for using VIA for triage of HPV infected women is
that visual evaluation of the cervix is poorly sensitive for detecting
CIN2+, especially if the lesions are small, as has been shown for colposcopy, which has an accuracy that seems to be much lower than
assumed before [4953]. An interesting study from South Africa
[54] provides an example of the use of VIA as a triage tool. Using
a very simple approach, women were randomized to one of three
study arms: (1) HPV testing: women with a positive test had triage
with VIA followed by cryotherapy unless this method revealed contraindications for cryotherapy such as suspicion of cancer, large
intraepithelial lesions, etc. that prompted to referal for specialized
evaluation; (2) conventional VIA followed by cryotherapy unless a
contraindication existed; and (3) control group followed with Pap
smear. After 12 months of follow-up, they found that the prevalence of CIN2+ lesions in the HPV testing plus cryotherapy group
was lower than in the other groups.
Using VIA as a diagnostic test for HPV infected women is more
complex than the previous approach. There would not be doubts
about the need of treating HPV positive women if VIA is positive,
but the decision becomes more complicated if VIA does not nd
abnormal changes in the cervical epithelium because, as previously
described, it could be missing early CIN2+ lesions. One option could
be to repeat the HPV test in one year and treat all women with

R. Herrero et al. / Vaccine 26S (2008) L49L58

positive tests assuming that this reects a persistent infection and


the risk of CIN is very high, but this approach has the potential of
losing many women who would not come back for the second test.

4. Conclusions
Immediate action needs to be taken in LAC to reduce the enormous burden of cervical cancer. We strongly recommend that each
country establishes a properly staffed and funded group dedicated
to cervical cancer control, responsible for developing and monitoring all activities of the program, including strict evaluation of the
compliance of all health providers. Screening and treatment should
be provided free of charge to all women. The different areas in the
country should be categorized according to their level of development and infrastructure to dene specic interventions to be
implemented in each area.
In places where no other methods are available or the existing
options have poor quality and limited coverage, we recommend
the implementation of visual inspection by primary care nurses
or physicians, with cryotherapy of positives after proper referral of
possible invasive cancers. The emphasis should be on complete coverage of women older than 2530 years, and implementation could
start with smaller demonstration projects. A VIA-based screening program still requires most of the programmatic components
described above and the use of VIA should be considered as an
interim approach while more sophisticated techniques such as HPV
testing can be introduced.
In areas where cytology is already established and has been
improved to the point of showing an impact on the incidence and
mortality, proper organization of the laboratories and, where feasible, centralization of the laboratories with the provision of adequate
equipment and quality assurance are paramount. Where followup can be assured, women with LSIL should be managed with
repeat cytology to prevent excessive burden to colposcopy services.
HSIL should be declared a public health priority with assurance of
follow-up and treatment for all women. Colposcopy services should
have the necessary staff, training, equipment and resources to evaluate and, if needed, treat in a timely fashion all women with HSIL.
Centralization of colposcopy services in high quality units should be
considered and such services should be restricted to women with
abnormalities and not used for primary screening.
In the near future, primary screening with HPV testing, with
its high sensitivity and negative predictive value should become
the standard of care, including algorithms using cytology or VIA
as secondary evaluations according to the local infrastructure and
resources. The new HPV test under development is expected to
be more affordable and to provide same-day results. All countries
should be aware of new developments in this eld, to incorporate
this promising technology when it becomes available. Demonstration projects and cost-effectiveness analysis are required, giving
serious consideration to self-collection of HPV specimens as an
alternative for women who live in isolated areas or refuse the
pelvic exam, and making sure only tests that have been properly validated are utilized. HPV testing will also be the method
of choice after mass vaccination is introduced. The collaboration
of governments, womens groups, academia, industry, donors and
international organizations could facilitate renewed efforts to control cervical cancer in LAC.

Disclosed potential conicts of Interest


None of the authors has disclosed potential conict of interest.

L57

References

[1] Parkin DM, Almonte M, Bruni L, Clifford G, Curado MP, Pineros


M. Burden
and trends of type-specic human papillomavirus infections and related diseases in the Latin America and Caribbean Region. Vaccine 2008;26.(Suppl 11):
L115.
[2] Franco EL. Commentary: Health inequity could increase in poor countries if
universal HPV vaccination is not adopted. BMJ 2007;335(7616):3789.
[3] Kane MA, Sherris J, Coursaget P, Aguado T, Cutts F. Chapter 15: HPV vaccine use
in the developing world. Vaccine 2006;24(Suppl 3):S1329.
[4] Herrero R, Schiffman MH, Bratti C, Hildesheim A, Balmaceda I, Sherman ME, et
al. Design and methods of a population-based natural history study of cervical
neoplasia in a rural province of Costa Rica: the Guanacaste Project. Rev Panam
Salud Publica 1997;1(5):36275.
[5] Hutchinson ML, Zahniser DJ, Sherman ME, Herrero R, Alfaro M, Bratti MC, et
al. Utility of liquid-based cytology for cervical carcinoma screening: results
of a population-based study conducted in a region of Costa Rica with a high
incidence of cervical carcinoma. Cancer 1999;87(2):4855.
[6] Schneider DL, Herrero R, Bratti C, Greenberg MD, Hildesheim A, Sherman ME,
et al. Cervicography screening for cervical cancer among 8460 women in a
high-risk population. Am J Obstet Gynecol 1999;180(2 Pt 1):2908.
[7] Ferreccio C, Bratti MC, Sherman ME, Herrero R, Wacholder S, Hildesheim A, et
al. A comparison of single and combined visual, cytologic, and virologic tests as
screening strategies in a region at high risk of cervical cancer. Cancer Epidemiol
Biomarkers Prev 2003;12(9):81523.
[8] Schiffman M, Herrero R, Hildesheim A, Sherman ME, Bratti M, Wacholder S,
et al. HPV DNA testing in cervical cancer screening: results from women in a
high-risk province of Costa Rica. JAMA 2000;283(1):8793.
[9] Davey E, Barratt A, Irwig L, Chan SF, Macaskill P, Mannes P, et al. Effect of study
design and quality on unsatisfactory rates, cytology classications, and accuracy in liquid-based versus conventional cervical cytology: a systematic review.
Lancet 2006;367(9505):12232.
[10] Almonte M, Ferreccio C, Winkler JL, Cuzick J, Tsu V, Robles S, et al. Cervical
screening by visual inspection, HPV testing, liquid-based and conventional
cytology in Amazonian Peru. Int J Cancer 2007;121(4):796802.
[11] Ferreccio C, Jeronimo J, Robles S, Winkler JL, Tsu V, Gonzales M, et al. Implementing Visual Inspection with Acetic Acid in the Field: The Challenge of
Standardization. 19th International Papillomavirus Conference, Florianapolis,
Brazil, September 1-7 2001. Abstracts book.
[12] Winkler JL, Lewis K, Del Aguila R, Gonzales M, Delgado JM, Tsu V, et al. Is magnication necessary to conrm visual inspection of cervical abnormalities? A
randomized trial in Peru. Rev Panam Salud Publica 2008;23(1):16.
[13] Luciani S, Winkler JL. Cervical Cancer Prevention in Peru: Lessons Learned from
the TATI Demonstration Project. Washington: PAHO; 2006.
S, Jeronimo J, Robles S. Effectiveness of cryother[14] Luciani S, Gonzalez M, Munoz
apy treatment for cervical intraepithelial neoplasia. Int J Gynecol Obstet
2008;101(2):1727.
[15] Ferreccio C, Corvalan A, Margozzini P, Viviani P, Gonzalez C, Aguilera X, et al.
Baseline assessment of the prevalence and geographical distribution of HPV
types in Chile using self-collected vaginal samples. BMC Public Health 2008
Feb 28;8(1):78.
[16] Ferreccio C, Prado RB, Luzoro AV, Ampuero SL, Snijders PJ, Meijer CJ, et al.
Population-based prevalence and age distribution of human papillomavirus
among women in Santiago, Chile. Cancer Epidemiol Biomarkers Prev 2004
Dec;13(12):22716.
[17] Salmeron J, Lazcano-Ponce E, Lorincz A, Hernandez M, Hernandez P, Leyva A,
et al. Comparison of HPV-based assays with Papanicolaou smears for cervical cancer screening in Morelos State, Mexico. Cancer Causes Control 2003
Aug;14(6):50512.
[18] Sarian LO, Derchain SF, Naud P, Roteli-Martins C, Longatto-Filho A, Tatti S, et
al. Evaluation of visual inspection with acetic acid (VIA), Lugols iodine (VILI),
cervical cytology and HPV testing as cervical screening tools in Latin America.
This report refers to partial results from the LAMS (Latin American Screening)
study. J Med Screen 2005;12(3):1429.
[19] Goldie SJ, Gafkin L, Goldhaber-Fiebert JD, Gordillo-Tobar A, Levin C, Mahe C, et
al. Cost-effectiveness of cervical-cancer screening in ve developing countries.
N Engl J Med 2005;353(20):215868.
[20] Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler CM. A 2year prospective study of human papillomavirus persistence among women
with a cytological diagnosis of atypical squamous cells of undetermined signicance or low-grade squamous intraepithelial lesion. J Infect Dis 2007 Jun
1;195(11):15829.
[21] Gravitt P, Coutlee F, Iftner T, Sellors J, Quint W, Wheeler CM. New Technologies
in Cervical Cancer Screening. Vaccine 2008;26(Suppl 10):K4251.
[22] Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet 2007 Sep 8;370(9590):890907.
[23] Wright Jr TC, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D. 2006
consensus guidelines for the management of women with abnormal cervical
cancer screening tests. Am J Obstet Gynecol 2007 Oct;197(4):34655.
[24] Santos C, Galdos R, Alvarez M, Velarde C, Barriga O, Dyer R, et al. One-Session
Management of Cervical Intraepithelial Neoplasia: A Solution for Developing
Countries. A Prospective, Randomized Trial of LEEP versus Laser Excisional
Conization. Gynecol Oncol 1996 Apr;61(1):115.
[25] Ronco G, Cuzick J, Pierotti P, Cariaggi MP, Dalla PP, Naldoni C, et al. Accuracy
of liquid based versus conventional cytology: overall results of new technolo-

L58

[26]
[27]

[28]

[29]
[30]

[31]

[32]

[33]

[34]

[35]

[36]
[37]

[38]
[39]

[40]

R. Herrero et al. / Vaccine 26S (2008) L49L58


gies for cervical cancer screening: randomised controlled trial. BMJ 2007 Jul
7;335(7609):28.
Castle PE, Wheeler CM, Solomon D, Schiffman M, Peyton CL. Interlaboratory
reliability of Hybrid Capture 2. Am J Clin Pathol 2004 Aug;122(2):23845.
Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G, Mayrand M-H, et
al. Overview of human papillomavirus-based and other novel options for
cervical cancer screening in developed and developing countries. Vaccine
2008;26(Suppl 10):K2941.
Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9: Clinical applications of HPV testing: A summary of meta-analyses. Vaccine 2006
Aug 21;24(Suppl 3):S7889.
Moscicki AB, Schiffman M, Kjaer S, Villa LL. Chapter 5: Updating the natural
history of HPV and anogenital cancer. Vaccine 2006 Aug 21;24(Suppl 3):S4251.
Flores Y, Bishai D, Lazcano E, Shah K, Lorincz A, Hernandez M, et al. Improving
cervical cancer screening in Mexico: results from the Morelos HPV Study. Salud
Publica Mex 2003;45(Suppl 3):S38898.
Longatto-Filho A, Erzen M, Branca M, Roteli-Martins C, Naud P, Derchain SF, et
al. Human papillomavirus testing as an optional screening tool in low-resource
settings of Latin America: experience from the Latin American Screening study.
Int J Gynecol Cancer 2006 May;16(3):95562.
Clavel C, Cucherousset J, Lorenzato M, Caudroy S, Nou JM, Nazeyrollas P, et al.
Negative human papillomavirus testing in normal smears selects a population
at low risk for developing high-grade cervical lesions. Br J Cancer 2004 May
4;90(9):18038.
Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al. The
elevated 10-year risk of cervical precancer and cancer in women with human
papillomavirus (HPV) type 16 or 18 and the possible utility of type-specic HPV
testing in clinical practice. J Natl Cancer Inst 2005 Jul 20;97(14):10729.
Bulkmans NW, Berkhof J, Rozendaal L, van Kemenade FJ, Boeke AJ, Bulk S, et al.
Human papillomavirus DNA testing for the detection of cervical intraepithelial
neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled
implementation trial. Lancet 2007 Nov 24;370(9601):176472.
Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K, et al. Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med
2007 Oct 18;357(16):158997.
Screening Technologies to Advance Rapid Testing (START) Project, Seattle, MA,
PATH, 2008.
Franco EL, Cuzick J, Hildesheim A, de Sanjos S. Chapter 20: Issues in planning
cervical cancer screening in the era of HPV vaccination. Vaccine 2006;24(Suppl
3):S1717.
Schiffman M. Integration of human papillomavirus vaccination, cytology, and
human papillomavirus testing. Cancer 2007 Jun 25;111(3):14553.
N, et al. InteFranco EL, Tsu V, Herrero R, Lazcano-Ponce E, Hildesheim A, Munoz
gration of Human Papillomavirus Vaccination and Cervical Cancer Screening in
Latin America and the Caribbean. Vaccine 2008;26(Suppl 11):L8895.
Hanisch R, Gaviria AM, Gustat J, Hagensee ME, Castro M, Sanchez GI. Evaluacin
del conocimiento que tienen las mujeres acerca de la citologa y los riesgos

[41]

[42]

[43]

[44]

[45]

[46]

[47]
[48]

[49]
[50]

[51]
[52]

[53]

[54]

de desarrollar cncer como consecuencia de la infeccin con el Papilomavirus


Humano (VPH). IV Encuentro de Investigacin en Enfermedades Infecciosas
Asociacin Colombiana de Infectologa. Medellin, Colombia, June 1012 2004.
Abstracts book.
Gaviria AM. Conocimientos de los estudiantes universitarios del Colegio Mayor
de Antioquia, Medelln, acerca del Papilomavirus humano. Rev Fac Nac Salud
Publica 2003;21(2):438.
Megevand E, Denny L, Dehaeck K, Soeters R, Bloch B. Acetic acid visualization of the cervix: an alternative to cytologic screening. Obstet Gynecol 1996
Sep;88(3):3836.
Sankaranarayanan R, Wesley R, Somanathan T, Dhakad N, Shyamalakumary B,
Amma NS, et al. Visual inspection of the uterine cervix after the application
of acetic acid in the detection of cervical carcinoma and its precursors. Cancer
1998 Nov 15;83(10):21506.
Visual inspection with acetic acid for cervical-cancer screening: test qualities
in a primary-care setting. University of Zimbabwe/JHPIEGO Cervical Cancer
Project. Lancet 1999 Mar 13;353(9156):86973.
Sankaranarayanan R, Esmy PO, Rajkumar R, Muwonge R, Swaminathan R,
Shanthakumari S, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu. India: a cluster-randomised trial Lancet
2007;370(9585):398406.
Claeys P, De Vuyst H, Gonzalez C, Garcia A, Bello RE, Temmerman M. Performance of the acetic acid test when used in eld conditions as a screening test
for cervical cancer. Trop Med Int Health 2003 Aug;8(8):7049.
Denny L, Quinn M, Sankaranarayanan R. Chapter 8: Screening for cervical cancer
in developing countries. Vaccine 2006;24(Suppl 3):S717.
N, et al. Worldde Sanjose S, Diaz M, Castellsague X, Clifford G, Bruni L, Munoz
wide prevalence and genotype distribution of cervical human papillomavirus
DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis 2007
Jul;7(7):4539.
Jeronimo J, Schiffman M. Colposcopy at a crossroads. Am J Obstet Gynecol 2006
Aug;195(2):34953.
Sideri M, Schettino F, Spinaci L, Spolti N, Crosignani P. Operator variability in
disease detection and grading by colposcopy in patients with mild dysplastic
smears. Cancer 1995 Nov 1;76(9):16015.
Massad LS, Collins YC. Strength of correlations between colposcopic impression
and biopsy histology. Gynecol Oncol 2003 Jun;89(3):4248.
Ferris DG, Litaker MS. Prediction of cervical histologic results using an
abbreviated Reid Colposcopic Index during ALTS. Am J Obstet Gynecol 2006
Mar;194(3):70410.
Gage JC, Hanson VW, Abbey K, Dippery S, Gardner S, Kubota J, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol 2006
Aug;108(2):26472.
Denny L, Kuhn L, De Souza M, Pollack AE, Dupree W, Wright Jr TC. Screenand-treat approaches for cervical cancer prevention in low-resource settings:
a randomized controlled trial. JAMA 2005 Nov 2;294(17):217381.

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